17{60 -(2,3-methylene-prop-1-en-1 yl)-steroids and 17{60 -(2,3-monohalomethylene and 2,3-dihalomethylene) derivatives thereof

ABSTRACT

WHEREIN R1 is H, carboxylic acyl groups of less than 12 carbon atoms, tetrahydropyran-2-yl, tetrahydrofuran-2-yl, or 4-methoxy tetrahydropyran-4-yl, R2, R3, and R4 are H, or a lower alkyl, preferably methyl, R5 is H, a lower alkyl such as methyl, ethyl or propyl, and X and Y are independently H, F, Br or Cl.   A physiologically active steroidal compound of the partial formula

United States Patent Crabb et a1.

[54] l7a-(2,3-METHYLENE-PROP-l-EN-l YL)-STEROIDS AND Una-(2,3- MONOHALOMETHYLENE AND 2,3- DIHALOMETHYLENE) DERIVATIVES THEREOF [72] Inventors: Pierre Crabb, Mexico; Ulrich Werner Graf, Cuemavaca, both of Mexico [73] Assignee: Syntex Corporation, Panama,

Panama [22] Filed: Jan. 19, 1970 [21] Appl. No.: 4,116

[52] US. Cl.....260/397.4, 260/239.55 R, 260/397.5,

260/999 [51] Int. Cl. ..C07c 169/08, C07c 169/22 [58] Field of Search ..lMachine Searched Steroids [56] References Cited UNITED STATES PATENTS 3,392,165 7/1968 Edwards et a1. ..260/239.55

[ 51 Aug. 8, 1972 3,392,166 7/1968 Edwards et al. ..260/239.55 3,385,871 5/1968 Edwards et a1. ..260/397.4 3,478,019 11/1969 Edwards ..260/23955 Primary Examiner-Henry A. French Attorney-Evelyn K. Merker and Gerard A. Blaufarb ABSTRACT A physiologically active steroidal compound of the partial formula R ,Hz R

CR1 a =c c l 1 1 Claims, No Drawings Typical compounds represented by Formula (III) include l7a-( 2,3 '-methylene-prop-l -en-1 -yl)- 1 7B- hydroxy-estr-4-en-3-one; l7a-(2',3'- monofluoromethylene-prop- 1 '-en- 1 '-yl)- 1 7fi-hydroxyestr-4-en-3-one; 3-desoxy- 17a-(2',3 '-methylene-prop- 1 '-en- 1 '-yl)-estr-4-en-3B, l 7B-diol; 3-desoxy- 1 7a- (2',3'1-en-1'-yl)-estr-4- en-3B,17B-diol; l7a-( 1 -methyl-2',3 '-methylene-prop- 1 -en- 1 -yl)-androst-4-en-3B, l 7B-diol; 17a-( l '-methyl- 2 ',3 '-monobromomethylene-prop-1 '-en-l '-yl)-androst-4-en-3B,17B-diol; 17a-(2,3 -methylene-prop-1 en-l '-yl)-17B-acetoxy-androst-4-en-3B-ol; 17a-(2',3'- monochloromethylene-prop- 1 '-en- 1 '-yl)-1 7B-acetoxyandrost-4-en-3B-ol; 33,173 -diacetoxy-17a-(2',3'- methylene-prop-l -en-1 '-yl)-androst-4-ene; 33,173- diacetoxy- 1 7a-( 2' ,3 '-chloromethylene-prop-1 '-en- 1 yl )-androst-4-ene; 1 7B-acetoxy- 1 7a-( 2 ,3 -methyleneprop-1 '-en-l '-en- 1 -yl )-androst-4-en-3-one; 17B- acetoxy- 1 7a-( 2 ,3 -monochloromethylene-prop-1 -en- 1 '-yl )-androst-4-en-3-one; 17a-(2 ,3 methylene-prop- 1 -en-1 -yl)-17B-hydroxy-androst-4-en-3-one; l7a-( 2 ,3 '-monofluoromethylene-prop-1 -en-1-yl)-l7B- hydroxy-androst-4-en-3 -one; 3-desoxy-17a-(2' ,-3 methylene-prop-l -en-l '-yl)- 1 7B-acetoxy-androst-4- ene; 3- -desoxy-17a-(2',3'-monofluoromethyleneprop-1 -en-1'-yl)-l7B-acetoxy-androst-4-ene; 17a-( 1'- methyl-2, 3-methylene-prop-1'-en-1-yl)-17B- (tetrahydrofuran-2-yloxy)-androst-4-en-3 -one; l7a-( 1 -methyl-2' ,3 '-monobromoethylene-prop-1 -en- 1 '-yl)- 1 7B-(tetrahydrofuran-2 '-yloxy)-androst-4-en-3-one;

3 B-acetoxy- 1 '7a-( 3 ,3 '-dimethyl-2' ,3 -methylene-prop- 1 -en- 1 -yl)-androst-4-en- 1 73-01; 3B-acetoxy-17a- (3 ,3 '-dimethyl-2' ,3 '-monochloromethylene-prop-l en-l -yl)-androst-4-en-173-01, and the like. The preferred compounds of Formula IH are those wherein R is H or methyl, R is 0x0 or the group wherein R9 is H or hydroxy, OR is hydroxy or acetate, and X and Y are independently H or F.

The novel 17a-methylene propenyl steroid of Formula (II) of this invention possess estrogenic activity and are useful in the treatment of various conditions in which such agents are indicated, such as estrogen deficiencies, memopause, and the like. These compounds can also be used in veterinary medicine in the same manner as known estrogens and in the control and regulation of fertility. In addition, these agents demonstrate anti-androgenic activity. They can be administered in the usual pharmaceutical compositions at dosages appropriate for the condition being treated.

The l7a-methylene propenyl steroids of Formula ([1]) demonstrate progestational, anti-estrogen and pituitary inhibition activity and are useful in the treatment of various menstrual disorders and in the control and regulation of fertility. They can be administered in the usual pharmaceutical compositions at dosages appropriate for the condition being treated.

The l7a-dihalomethylene propenyl steroidal compounds of this invention are prepared by a one-step dihalocarbene insertion reaction wherein a 170:- propadiene or a l7a-alkyl substituted propadienyl steroid is reacted with a dihalocarbene precursor as follows:

wherein R R R R R X and Y are as defined above.

The l7a-dihydromethylene propenyl derivatives can be prepared by reaction of the 17a-propadiene steroid in the above illustrated manner, with his (bromomethyl) mercury in boiling benzene. The HF, HBr and HCl deriva' lves can, for example, be prepared by reduction of the appropriate 17a-dihalomethylene steroid with tri-n-buiryltin hydride in the presence of dit-butyl peroxide in mixture with an inert organic solvent such as, for example, ether, benzene, or toluene, at temperatures in the range of about from 30-120 C.

The 17a-alkyl substituted alkadiene-estra-1,3,5( l0)- triene starting materials in the above described reactions are disclosed in US. Pat. No. 3,392,165, incorporated herein by reference. Accordingly, these starting materials are themselves prepared from 17a-dihalocyclopropyl estratrienes. By one disclosed procedure, a 17a-diha1ocyclopropyl estratriene is reacted with an alkyl lithium reagent such as butyl lithium in an inert solvent medium such as a hydrocarbon, ether, chlorinated hydrocarbon, and mixtures thereof. The alkyl lithium reagent is present in a molar excess and the reaction is conducted at room temperature or above for about 3 to 24 hours or more.

The 17a-alkadiene andr0st-4-ene and the l7a-alkadiene estr-4-ene starting materials in the above described reactions are disclosed in US. Pat. No. 3,392,166, incorporated herein by reference. Accordingly, these starting materials are themselves prepared from l7a-dihalocyclopropyl compounds. By one such procedure, a 17a-dihalocyclopropyl estr-4- ene is reacted with a molar excess, preferably about 2 to 10 molar equivalents of an alkyl lithium such as butyl lithium. The reaction is carried out in an inert reaction medium such as dioxane, tetrahydrofuran, hexane, and the like, at a temperature of from 40 to 0 C., for about 1 to 24 hours or more, preferably at 30 C. for about 1 hour.

The dihalo carbenes can be generated in any suitable manner, such as for example, from alkali metal salts of trihaloacetic acid, such as sodium trichloroacetate, sodium chlorodifluoro acetate, sodium fluorodichloro acetate, and the like, dissolved in a suitable solvent. Other suitable dihalo carbene precursors include, for example, phenyl (tribromomethyl) mercury, phenyl (trichloromethyl) mercury, phenyl (fluorodichloromethyl) mercury-sodium iodide, phenyl (chlorodibromomethyl) mercury, phenyl (fluorodibromomethyl) mercury, trimethyl (trifluoromethyl) mercury-sodium iodide, bromoformpotassium t-butoxide and the like.

The carbene insertion reaction is conducted under anhydrous conditions in an inert solvent. The precursor is added to the steroid admixed with a suitable solvent heated to the described reaction temperature. The steroid can alternatively be added to a solution of precursor and solvent and the mixture subsequently heated. The particular solvent, as well as the temperature of reaction, will depend upon particular carbene precursor selected. Different precursors liberate carbene under different conditions.

The alkaline metal salts of trihaloacetic acid liberate the carbene by way of a thermal decarboxylation. The metal salt is dissolved in a suitable solvent such as diethylene glycol dimethyl ether, diglyme, triethylene glycol dimethylether, and the like, the steroid added, and the mixture heated to the appropriate temperature. In the case of diglyme, the salt solution is heated to between 120 to 165 C., in the presence of the steroid. The temperatures to which the other aforementioned solvents are desirably heated are available from the literature or can easily be determined by routine experimentation. The bromoform-potassium t-butoxide precursor, contains bromoform in an excess of 20-50 equivalents. Said precursor is dissolved in a suitable solvent such as tetrahydrofuran cyclohexane, t-butanol, and the like, and reacted at temperatures in the range of about from to C., and for best results about from 10 to 0 C. The phenyl (trihalomethyl) mercury precursors liberate carbene upon thermal treatment in a suitable solvent, such as boiling benzene. The carbene can be generated from phenyl (trihalomethyl) mercury at lower temperatures, e.g., 30 C. when heated in benzene in the presence of sodium iodide. The trimethyl (trifluoromethyl) tin precursor forms the carbene under similar thermal conditions. The trihalomethyl tin generates carbene when dissolved in a suitable solvent such as benzene, toluene or the like, and heated at reflux in the presence of sodium iodide. Other suitable procedures for generating carbenes are described in the J. of Am. Chem. Soc., Vol. 82, page 1188 (1960) and Kirmse, Carbene Chemistry, Vol 1, Academic Press, pages 145-169 (1964). Still other precursors will be readily apparent to those of ordinary skill in the art.

Generally, one to 10 molar equivalents of the carbene precursor in a suitable solvent is reacted with the 17a-propadienyl steroid. However, as much as 20 and even 50 molar equivalents of the carbene precursor can be reacted with the steroid.

The Wot-methylene propenyl-17B-hydroxy compound of this invention may be converted to the corresponding 1 7B-acyloxyl 7,6-( tetrahydropyran-2 yloxy) or l7B-(tetraydrofuran-2-yloxy) derivative by conventional methods prior to preparing the 17amethylene propenyl steroids or can be esterified or etherified thereafter. It is preferred, however, to carry out the carbene insertion reaction with the 17B-acyloxy steroid, and then convert the thus obtained steroid to the l7B-hydroxy, or other derivatives.

The substituent at the 3-position of the estratriene nucleus can be a hydroxy group or an etherified group, e.g., methoxy, tetrahydropyran-2-yloxy, tetrahydrofuran-2-yloxy, cyclopentyloxy, and the like. These derivatives can be prepared prior to the preparation of the novel 17a-methylene propenyl derivatives or can be formed thereafter by conventional methods. Thus, treatment with an appropriate carboxylic acid anhydride such as acetic anhydride in pyridine with a 3,l7fi dihydroxy estratriene yields the 3-acyloxy-l7B- hydroxy derivative selectively. Use of an acid anhydride in the presence of the corresponding acid and an acid catalyst such as p-toluenesulfonic acid yields the 3,17B-diacyloxy derivatives. This diester can then be selectively saponified, after the carbene reaction, through the use of methanolic potassium bicarbonate, to yield the corresponding 3-hydroxy-17B-acyloxy derivative. Similarly, etheritication can be performed via conventional procedures. Thus, treatment of the hydroxy derivative with dihydropyran in the presence of an acid catalyst such as p-toluenesulfonic acid, ptoluenesulfonyl chloride, dinitrobezene sulfonic acid or the like, yields the corresponding tetrahydropyran-2- yloxy derivative. Formation of the monotetrahydropyranyl ether can be accomplished by selective protection of other hydroxy groups as through ester formation, in the manner described above, with alkaline hydrolysis of such ester groups after formation of the ether, if desired. Formation of 3-methoxy deriva tives will be realized through the use of dimethylsulfate and potassium hydroxide in the conventional manner.

The 3-keto group of the 17B-methylene propenyl estrene or androstene may be reduced with sodium borohydride, lithium aluminum tri(t-butoxy) hydride, or the like to obtain the 3B-hydroxy steroid. The resulting 3B-hydroxy group may then be etherified by treatment with dihydropyran or dihydrofuran and an acid catalyst or esterified by treatment with an appropriate carboxylic acid anhydride such as acetic acid anhydride, in pyridine and the like. Other techniques will be readily apparent to those skilled in the art.

The 17,8-hydroxy estrene or androstene can be converted to the corresponding 17/3-acyloxy, 17B- tetrahydropyran-Z-yloxy, or l7B-tetrahydrofuran-2- yloxy derivatives by conventional methods, such as those already set forth. The 3-desoxy derivatives of Formula (111) can be prepared from the corresponding 3-keto derivatives by thioketalization followed by desulfurization with Raney nickel.

A further understanding of the invention can be had from the following examples.

EXAMPLE 1 From a solution of 3.4 g. (20 mm.) of sodium difluorochloroacetate in 30 ml. of diglyme (distilled over potassium hydroxide pellets), about 10 ml. of the diglyme is distilled off at 30 to 40 C. in vacuum. The remaining solution is transferred to a dropping funnel which is placed onto a 3-neck flask. In the flask, 700 mg. (2 mm.) of l7l3-acetoxy-l7a-(propadien-1-yl)- estr-4-en-3-one is dissolved in 17 ml. of diglyme and heated to the boiling point. The sodium salt solution is added dropwise within 1 hour while a total of 40 ml. of diglyme is distilled from the reaction mixture at normal pressure. The reaction mixture if refluxed for 10 minutes, cooled, filtered and evaporated. The crude product is separated by preparative thick-layer chromatography in hexane-ethyl acetate. About 300 mg. of 1 7B-acetoxy- 1 7a-( 2,3 difluoromethylene-propl en-l'-yl)-estr-4-en- 3-one and mg. of crude unreacted 17a-propadiene is obtained. The difluoromethylene propenyl estrenone was recrystallized from acetone-water.

in a like manner, 17B-hydroxy-l7a-(propadien-l'- yl)-estr-4-en-3-one, 17B-(tetrahydropyran-2'-yloxy)- l 7a-(propadien-l -yl)-estr 4-en-3-one, 17B-acetoxyl7a-(propadien-l 'yl )-androst-4-en-3-one are reacted with sodium difluorochloroacetate to yield the corresponding difluoromethylene derivatives.

EXAMPLE 2 To a stirred solution of g. of sodium trichloroacetate in 100 ml. of diethylene glycol dimethyl ether, is added 0.8 grams of l7a-(propadien-l '-yl)-l7B-acetoxy-androst-4-en-3-one and the mixture heated to 130 C. and reacted for approximately 2 hours. The mixture is subsequently cooled, and poured into cold water. The solid which forms is collected, washed with water and dried to yield l7a-[2',3'- dichloromethylene-prop-l '-en-l -yl -androst-4-en-3- one.

In a like manner l7a-(propadien-l-yl)-l7B- (tetrahydropyran-2-yloxy)-androst-4-en-3-one, 17a- (propadien-l '-yl 1 7B-( tetrahydrofuran-2 -yloxy )-androst-4-en-3-one and l7a-(propadien-l'-yl)-l7B-4'- methoxy tetrahydropyran-4-yloxy)-a.ndrost-4-en-3- one are reacted with sodium trichloroacetate, yielding l7a-( 2 ,3 -dichlorornethylene-prop-l -en-l'-yl)-17B- (tetrahydropyranyl-2-yloxy)-androst-4-en-3-one, 17a- (2',3 -dichloromethylene-propl '-en-l '-yl 1 7B- (tetrahydrofuran-Z-yloxy)-androst-4-en-3-one and l7a-(2 ,3 '-dichloromethylene-prop-l -en- 1 '-yl)- 1 7B- (4-methoxy tetrahydropyran-4-yloxy)-a.ndrost-4-en- 3-one.

Repeating the above procedure substituting sodium tribromoacetate for sodium trichloroacetate, the corresponding dibromomethylene-propenyl derivatives are obtained.

EXAMPLE 3 To a refluxing solution of l g. of l'la-(propadien-l yl)-l7B-hydroxy-estr-4-en-3-one in 10 ml. of diethylene glycol dimethyl ether is added over a 2 hour period in dropwise fashion with stirring, a solution of 35 equivalents of sodium fluorodichloroacetate in 40 ml. of diethylene glycol dimethyl ether. After refluxing for an additional hour, the mixture is filtered. The filtrate is evaporated to dryness and the residue is chromatographed on alumina eluting with methylene chloride to yield l7a-(2,3-fluorochloromethyleneprop-l -en-l -yl l 7B-hydroxyestr-4-en-3-one.

EXAMPLE 4 To a solution of 1.4 equivalents of phenyl (fluorodichloromethyl) mercury and 1.4 equivalent NaI in ml. of benzene is added about 0.3 g. of 175- acetoxy-17a-(propadien-l -yl)-estr-4-en-3-one. The mixture is heated to reflux and allowed to react under reflux for 18 hours. Thereafter, the mixture is cooled to room temperature and filtered. The filtrate is evaporated to dryness and the residue chromatographed on alumina eluting with benzene to yield 173- acetoxy- 1 7oz-( 2 ,3 -fluorochloromethylene-prop-l '-en- 1 -yl)-estr-4-en-3-one.

The above procedure is repeated using phenyl (chlorodibromomethyl) mercury, phenyl (trichloromethyl) mercury and phenyl (tribromomethyl) mercury to yield the fluorobromo,

bromochloro, dibromo and dichloro methylene propenyl derivatives respectively.

EXAMPLE 5 To a stirred solution of 2 grams of l7B-acetoxy- 1 7a- (propadien-l '-yl)-estr-4-en-3-one in 100 ml. of cyclohexane, cooled to 0 C. is added 20 equivalents CH Br and 20 equivalents of solid t-butoxide. The mixture is allowed to react for 6 hours at 0, poured into water and crude product, isolated by extraction with ethyl acetate. The resulting product, 17B-acetoxy- 1 7a- (2,3 -dibromomethylene-prop-l -en-1 '-yl)-estr-4-en- 3-one is purified by chromatography on alumina and recrystallized from pentane.

EXAMPLE 6 To a refluxing solution of 2 grams of 17B-acetoxy-l7 a-(propadien-l '-yl)-androst-4-en-3-one in 50 ml. of benzene is added in dropise fashion 15 molar equivalents of bis(bromomethyl) mercury in 20 ml. of benzene. The mixture is allowed to boil for 18 hours, cooled to room temperature and filtered. The filtrate is washed with water and evaporated to dryness and the residue chromatographed on alumina eluting with benzene and benzene-ether mixtures to yield 171?- acetoxyl 7a-(2' ,3 '-dihydromethylene-prop-l -en-l yl)-androst-4-en-3-one.

EXAMPLE 7 One gram of 17B-acetoxy-l 7a-(2 ,3 fluorochloromethylene-prop-l '-en-l -yl )-estr-4-en-3 one produced by the method of Example 4 is dissolved in 25 ml. of benzene containing 0.2 g. of di-t-butylperoxide to which 14 molar equivalents of trin-butyltin hydride is added and the mixture heated to C. The mixture is allowed to react at this temperature for 18 hours, cooled, filtered, washed with water, dried and evaporated under vacuum. The residue is chromatographed on neutral alumina, eluting with hexane and hexane-benzene mixtures to yield 17B-acetoxy-l7a- (2 ,3 -monofluoromethylene-prop-l -en-l '-yl )-androst-4-en-3-ol.

In a similar manner l7B-acetoxy-l7a-(2',3 'dichloromethylene-prop-l '-en-l '-yl )-estr-4-en-3-one and l7B-acetoxyl 7a-(2,3 '-dibromomethylene-propl'-en-l-yl)-estr-4-en-3-one are reacted to yield 173- acetoxy- 1 7a-( 2 ,3 '-hydrochloro-methylene-prop-l en-l-yl)-estr-4-en-3-one and l7B-acetoxyl7oz-(2',3- hydrobromomethylene-prop-l '-en-l '-yl )-estr-4-en-3- one.

EXAMPLE 8 One gram of l7B-acetoxy- 1 7a-( 2 ,3 difluoromethylene-prop-l '-en-l '-yl )-estr-4-en-3-one produced following the procedure of Example 1 is allowed to stand at room temperature for 15 hours with 1 g. of potassium bicarbonate in 10 ml. of water and ml. of methanol. At the end of this time, the methanol is evaporated under reduced pressure and the residue extracted with ethyl acetate and water. Evaporation of the ethyl acetate from these extracts yields 17B- hydroxyl 7a-(2,3 '-difluoromethylene-prop-l '-en-l yl)-estr-4-en-3-one which is collected by filtration and recrystallized from acetone:hexane.

EXAMPLE 9 EXAMPLE Two milliliters of dihydropyran are added to a solution of l g. of 17B-hydroxy-l7a-(2',3'- difluoromethylene-prop-l '-en-l -yl)-estr-4-en-3-one (prepared by the procedure of Example 8) in ml. of benzene. About 1 n11. is removed by distillation to remove moisture and 0.4 g. of p-toluene sulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane to yield 17B-(tetrahydropyran-2 '-yloxy)- l 7a-(2 ,3 difluoromethylene-prop-l '-en-1 -yl)-estr-4-en-3 -one which is recrystallized from pentane.

Similarly, following the above procedure, other 173- hydroxy- 1 7a-(dihalomethylene-prop- 1 '-en-1 '-yl) compounds are converted to the corresponding 17B- (tetrahydropyran-2'-yloxy) derivatives, e.g. 17B- (tetrahydropyran-Z'-yloxy)-l 7a-( 2' ,3 dichloromethylene-prop- 1 '-en- 1 '-yl)- l 8-methylestr-4- en-3 -one, 3 B-acetoxy- 1 7/3-( tetrahydropyran-2'-yloxy l7a-(2 ,3 '-di bromomethylene-prop-l '-en-l '-yl)-androst-4-ene, and the like.

EXAMPLE 11 A solution of l g. of l7B-hydroxy-17a-(2,3'- difluoromethylene-prop-l '-en-l -yl)-estr-4-en3-one (prepared by the procedure of Example 8) in 50 ml. of tetrahydrofuran is added over a 30 minute period to a stirred suspension of 1 g. of lithium aluminum hydride in 50 ml. of anhydrous tetrahydrofuran and this mixture is heated at reflux for 2 hours. To the mixture is added 5 ml. of ethyl acetate and 2 ml. of water. Sodium sulfate is next added, the mixture filtered and the solid thus collected is washed with hot ethyl acetate. The combined organic solutions are then evaporated to yield 1 7a-( 2,3 '-difluoromethylene-prop-l '-en- 1 -yl)- estr-4-en-3B,l7B-diol, which is further purified through recrystallization from acetonezhexane.

Use of this procedure with the other 3-keto-17B- hydroxy compounds described above will similarly yield the 33,17B-diol derivatives, e.g. l7a-(3'-methyl- 2' ,3 '-dichloromethylene-prop-l '-en-l '-yl)-estr-4-en- 313,17B-diol, 1 7a-( 2 ,3 -bromochloromethylene-propl '-en-1 -yl)-androst-4-en-3B, l 7B-diol, and the like.

EXAMPLE 12 To a solution of l g. of l7a-(2',3'-

difluoromethylene-prop-l '-en- 1 '-yl )-estr-4-en-3B, 1 7B- diol (prepared according to the method of Example 11) is added 1 g. of acetic anhydride in 50 ml. of pyridine and the mixture allowed to stand for 5 hours. At the end of this time, the reaction mixture is precipitated with water and the precipitate filtered off and dried. The solid product 3B-acetoxy-17a-(2',3 difluoromethylene-prop-l '-en- 1 -yl)-estr-4-en- I 76-01, is then recrystallized from acetone-hexane.

EXAMPLE 13 To a solution of 0.5 g. of 17/3-acetoxy-l7a-(2,3- difluoromethylene-prop-l '-en-1 -yl)-estr-4-en-3 -one in 50 ml. of tetrahydrofuran is added over a 30 minute period, 2 grams of lithium tri-t-butoxy aluminum hydride in 50 ml. of anhydrous tetrahydrofuran, and the mixture heated at reflux for 2 hours. To this mixture 5 ml. of ethyl acetate and 2 ml. of water are then added to the mixture. Sodium sulfate is next added, the mixture filtered and the solid thus collected washed with hot ethyl acetate. The combined organic solutions are evaporated to yield 17B-acetoxy-l7a-(2',3- difluoromethylene-prop-l -en-1 "yl)-estr-4-en-3B-ol, which is further purified through recrystallization from acetonezhexane.

The thus obtained l7B-acetoxy-estr-4-en-3-ol is reacted with 10 ml. of dihydropyran in the presence of 0.1 g. of p-toluenesulfonyl chloride and 25 ml. of ether, to yield the corresponding 3B-(tetrahydropyran-2'- yloxy)-1 7a-( 2 ',3 -difluoromethylene-prop-l '-en-l yl)-l7B-acetoxy-estr-4-one. Substituting dihydrofuran in the above reaction the corresponding 33- (tetrahydrofuran-2'-yloxy) derivative is obtained. The 3B-tetrahydropyran-l7B-acetoxy derivative is hydrolyzed to the 17B-hydroxy form by reaction with potassium hydroxide and methanol under reflux.

Similarly, following the procedures outlined above, other 17a-( 2,3 '-difluoromethylene-prop-l '-en-l '-yl estI-4-en-3-ols are converted to the corresponding 38- oxy derivatives, e.g. 3B-(tetrahydropyran-2'-yloxy)- 1 7a-( 2' ,3 -difluoromethylene-prop-l '-en-l '-yl )-estr-4- en-3-ol, 3 B-(tetrahydrofuran-2-yloxy l 7a-(2 ',3 difluoromethylene-propl '-en-l '-yl )-estr-4-en-3-ol, 3B-(4'-methoxytetrahydropyran-4 '-yloxy)- 1 7a-( 2,3 difluoromethylene-propl '-en- 1 '-yl )-estr-4-en- 1 73-01, 3B-(tetrahydropyran-2-yloxy)-17a-(2',3'- difluoromethylene-prop-l -en-l '-yl )-androst-4-en-1 7 3-01, 3,8-(tetrahydrofuran-2-yloxy)-17a-(2',3- difluoromethylene-prop-l -en-1 -yl)-androst-4-en-l 7 [3-01, and the like.

EXAMPLE 14 A solution of l g. of 3-methoxy-l7a-(l-methylpropadien-l '-yl)-estra-1 ,3,5( l0)-t1'ien 1 73-01 in ml. of benzene containing 1.2 equivalents of phenyl (trichloromethyl) mercury is heated to reflux for 18 hours. The cooled mixture is filtered, washed with water, dried and then evaporated to dryness. The 3- methoxy-l 7a-( 1 '-methyl-2 ',3 -dichloromethyleneprop-l'-en-l'-yl)-estra-l,3,5(lO)-trien-l7B-ol is then recrystallized from acetone-ether.

Similarly, 3-acetoxy- 1 7a-(propadien-1 '-yl)-estra- 1,3,5 l)-trien- 173-01, 3-acetoxyl 7a-(propadien-l yl)-17l3-propionoxyestra-l,3 ,5( l0)-triene,

3-acetoxyand 3-acetoxy-17a-(propadien-1 '-y1)-18- 5 methylestra-1,3,5(l0)-trien-l7B-ol is reacted with phenyl (trichloromethyl) mercury to yield the corresponding l I 17a-( 2 ',3 -dichloromethylene-prop-l 'en- -yl) derivatives.

(propadien-l'-yl)-estra-1,3,5(10)-trien-3-ol in 50 ml. of dimethoxyethane is added 4 molar equivalents of phenyl (fluorodichloromethyl) mercury, 4 molar equivalents of sodium iodide. After refluxing for 18 hours, the mixture is filtered, washed with water and evaporated to dryness, and the residue chromatographed on alumina, eluting with benzene and benzene methylene chloride to yield 17B-acetoxy-17a-(2,3- fluorochloromethylene-prop-1 -en-l '-yl )-estra- 1 ,3 ,5

chlorobromo derivatives are obtained, e. g.

0 )-trien-3-ol.

In a similar manner 3-methoxy-17a-(propadien-1 '-yl l 7B-acetoxyl 8- methylestra-1,3 ,5(10)-triene,

3-methoxy- 1 7a-( 1 'methyl-propadien-l -yl)- 1 7B- acetoxy-estra-l ,3 ,5( 10)-triene, l ,3,5( 10 )-triene,

3-methoxy- 1 7a-( 1 3 '-dimethyl-propadien-1 -y1)- 17B-acetoxy-18-ethylestra-l ,3 ,5(10)triene,'

3, 17B-diacetoxy-l7a-(propadien-1 '-yl)-estral,3,5(10)-triene,

1 7a-( 1 '-methyl-propadien- 1 '-yl)-17B-acetoxy-estr- 4-en-3-one, l7a-( propadien-l '-yl)-17/3-acetoxy-androst-4-en-3- one, 17a-(propadien-1 -y1)-l7,B-hydroxy-l 8-methyl-androst-4-en-3-one, and

l7a-( 2',3 -fluorochloromethylene-prop-1 -en-1 yl)-1 7,8-hydroxy-l 8-methyl-estr-4-en-3-one.

Substituting phenyl (chlorodibromomethyl) mercury the above procedure, the corresponding 17B-acetoxy- 1 7a-( 2 ',3 '-chlorobromomethyleneprop-l '-en-1'-y1)-estra-l,3,5( l0)-triene-3-ol,

3-methoxy-1 7a-( 2 ',3 '-chlorobromomethylene-prop- 1-en-1-yl)-l8-methyl-estra-1,3,5(l0)-triene,

3-methoxy- 1 7a-( 1 '-methyl-2',3

chlorobromomethylene-prop-1 -en-1 -yl)-17B- acetoxy-estral ,3 ,5( 10)-triene,

chlorobromomethylene-prop-1 '-en-1 '-yl)-1 7B- acetoxy-l8-ethyl-estra-1,3,5( l0)-triene, etc.

By using the phenyl (trichloromethyl) mercury in the foregoing procedure, the corresponding dichloro derivatives are obtained, e.g.

1 7B-acetoxy-1 7a-( 2 ',3 '-dichloromethylene-prop-1 en-l-yl)-estra-1,3,5( 10)-trien-3-ol.

EXAMPLE 16 A solution of 1 g. of l7B-acetoxy-l7a-(2,3- fluorochloromethylene-prop-l -en-1 'yl)-estral ,3,5 (l0)-trien-3-ol (prepared by the method of Example 15) in 60 ml. of anhydrous ether is treated with 7.5 molar equivalents of ethylmagnesium bromide in ether and after a few minutes, with 7.5 molar equivalents of chloroacetate. The mixture is allowed to stand at room temperature for 15 hours, then diluted with water, and extracted with methylene chloride. The extracts are washed with water to neutrality, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with etherzhexane to yield 3,17B-diacetoxy-17 a-( 2 ,3 -fluorochloromethylene-prop- 1 -en-1 '-yl estra-1,3,5(l0)-triene which is recrystallized from acetonezhexane.

The above procedure is repeated substituting chloropropionate for chloroacetate and the corresponding 3-propionoxy-17B-acetoxy-estratriene derivative is obtained.

EXAMPLE 17 Two milliliters of dihydropyran are added to a solution of 1 g. of 17B-acetoxy-17a-(2,3'- fluorochloromethylene-prop-1 '-en-1 -y1)-estra- 1 ,3,5 (10)-trien-3-ol, (prepared by the procedure of Example 15) in 15 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of ptoluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for 4 days, and then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is chromatographed on neutral alumina, eluting with hexane to yield 3-tetrahydropyran-2'-yloxy-l7B- acetoxy-l 7a-( 2 ',3 -fluorochloromethylene-prop-1 '-en- 1 -yl)-estra-1,3,5( 10)-triene.

Substituting dihydrofuran for dihydropyran in the above reaction, the corresponding 3-(tetrahydrofuran- 2-y1oxy) derivative is obtained.

EXAMPLE 18 A solution of one equivalent of l7B-acetoxy l7a- (2 ',3 '-fluorochloromethylene-prop-1 -en- 1 '-y] )-estral,3,5(10)-trien-3-ol (prepared by the procedure of Example 15) in 30 ml. of benzene is heated to reflux and about 2 ml. removed by distillation to eliminate moisture. The mixture is cooled to room temperature and 1 g. equivalent of sodium hydride is added, followed by the dropwise addition of 1.5 chemical EXAMPLE 19 A solution of 1 g. of 3-(tetrahydropyran-2'-yloxy)- l 7B-acetoxy- 1 7a-( 2 ',3 'fluorochloromethylene-propl-en-1-yl)-est1'a-1,3,5(l0)-triene, (prepared following the procedure of Example 17) in 50 ml. of methanol is heated at reflux for 3 hours with a solution of 0.2 grams of potassium hydroxide in 1 ml. of water. The reaction mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water to neutrality and dried to yield 3- (tetrahydropyran-2 '-yloxy 1 7a-( 2 ',3 fluorochloromethylene-prop-l '-en-l '-yl)-estral,3,5(10)-trien-l7Bol.

Substituting a 3-( tetrahydrofuran-2'-yloxy)-l7B- acetoxy-estratriene in the above reaction, the corresponding 3-(tetrahydrofuran-2-yloxy)-17B-ol is obtained.

The 3-(tetrahydropyran-2'-yloxy)-l7a-(2',3'- fluorochloromethylene-prop-1 -en-l -yl)-estra- 1,3,5(10)-trien-17B-ol obtained above is alternatively hydrolyzed with concentrated HCl in aqueous acetone to the corresponding 3,17B-diol. The thus obtained diol is reacted with acetic anhydride in pyridine to yield the 3-acetoxy-l 7B-hydroxy derivative.

The 3-acetoxy-estral,3,5-trien-l 7B-ol derivative is then reacted with dihydropyran in benzene according to the procedure of Example 16 to yield 3-acetoxy-l7fl -(tetrahydropyran-2 -yloxy 1 7a-( 2 3 fluorochloromethylene-prop-1 '-en-l '-yl)-estral ,3 ,5 10)-triene.

EXAMPLE 20 A mixture of 2 grams of l7B -acetoxy-l7a-(2,3'- fluorochloromethylene-prop-1 '-en-l '-yl)-estra-1,3 ,5 l0)-trien--trien-3-ol in 8 ml. of pyridine and 4 ml. of benzoyl chloride is heated at steam bath temperatures for 1 hour. The mixture is then poured into ice water and the solid which forms is collected by filtration, washed with water and dried to yield 3-benzoyloxy-l7B -acetoxy- 1 7a-( 2 ',3 -fluorochloromethylene-propl en-l 'l,3,5( l0)-triene which is further purified through recrystallization from acetone-hexane:hexane.

The use of this process with the other 3-hydroxy compounds of the present invention will similarly yield the corresponding 3-benzoyloxy derivatives.

Obviously many modifications and variations of the invention described hereinabove and in the appended claims can be made without departing from the essence and scope thereof.

What I claim is:

1. A compound selected from compounds of the formulas:

LII

wherein R is H, carboxylic acyl group of less than 12 carbon atoms, tetrahydropyran-Z-yl, tetrahydrofuran- 2-yl or 4-methoxy tetrahydropyran-4-yl; R R and R are independently H or a lower alkyl; R is H or lower alkyl; R is H, lower alkyl, carboxylic acyl having less than 12 carbon atoms, cyclopentyl tetrahydropyran-2- yl or tetrahydrofuran-2-yl; R is oxo, or the group II n wherein R is hydrogen, hydroxy, tetrahydropyran-2'- yloxy, tetrahydrofuran-2'-yloxy or a carboxylic acyloxy group containing less than 12 carbon atoms, R, is H or methyl and X and Y are independently selected from the group consisting of H, F, Br and Cl.

2. The compound of claim 1, Formula III, wherein R R R R and R are hydrogen, and R is methyl.

3. The compound of claim 1, Formula III, wherein R is acetoxy, R is methyl, R R and R are hydrogen and R is methyl.

4. The compound of claim 1 wherein R R and R are selected from the group consisting of H, or methyl.

5. The compound of claim 4 wherein R R and R are H.

6. The compound of claim 1, Formula III, wherein R is H.

7. The compound of claim 1 wherein R is H.

8. The compound of claim 1 wherein R R R and R are H.

9. The compound of claim 1, Formula III, wherein R2, R3 R41 R5 and R8 are H 10. The compound of Formula II of claim 1, wherein OR is hydroxy, R is H, R 0 is hydroxy or methoxy and X and Y are independently selected from the group consisting of H and F.

l l. The compound of Formula III of claim 1, wherein OR is hydroxy or acetate, R is H or methyl, R is oxo or the group wherein R is or hydroxy and X and Y are independently selected from the group consisting of H and F. 

2. The compound of claim 1, Formula III, wherein R1, R2, R3, R4, and R5 are hydrogen, and R8 is methyl.
 3. The compound of claim 1, Formula III, wherein R1 is acetoxy, R2 is methyl, R3, R4, and R5 are hydrogen and R8 is methyl.
 4. The compound of claim 1 wherein R2, R3, and R4 are selected from the group consisting of H, or methyl.
 5. The compound of claim 4 wherein R2, R3, and R4 are H.
 6. The compound of claim 1, Formula III, wherein R8 is H.
 7. The compound of claim 1 wherein R5 is H.
 8. The compound of claim 1 wherein R2, R3, R4 and R5 are H.
 9. The compound of claim 1, Formula III, wherein R2, R3, R4, R5 and R8 are H.
 10. The compound of Formula II of claim 1, wherein OR1 is hydroxy, R5 is H, R6O is hydroxy or methoxy and X and Y are independently selected from the group consisting of H and F.
 11. The compound of Formula III of claim 1, wherein OR1 is hydroxy or acetate, R5 is H or methyl, R7 is oxo or the group wherein R9 is H or hydroxy and X and Y are independently selected from the group consisting of H and F. 